rs373428732
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_000038.6(APC):c.2627G>A(p.Arg876Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000601 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R876G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.2627G>A | p.Arg876Gln | missense_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.2627G>A | p.Arg876Gln | missense_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000518 AC: 13AN: 250804Hom.: 0 AF XY: 0.0000738 AC XY: 10AN XY: 135534
GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461884Hom.: 0 Cov.: 33 AF XY: 0.0000688 AC XY: 50AN XY: 727242
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74304
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 11, 2024 | In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with papillary renal cell carcinoma and in an individual with breast cancer (PMID: 29684080, 35264596); This variant is associated with the following publications: (PMID: 21901162, 24142997, 22895193, 35264596, 27930734, 36243179, 35534704, 29684080) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 05, 2023 | In the published literature, this variant has been reported in individual with breast cancer (PMID: 35264596 (2022)) and myelodysplastic syndrome (PMID: 24142997 (2013)). The frequency of this variant in the general population, 0.00014 (7/50496 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Familial adenomatous polyposis 1 Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 15, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 13, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 30, 2023 | This missense variant replaces arginine with glutamine at codon 876 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with kidney cancer (PMID: 29684080). This variant has been identified in 15/282206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 03, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2023 | Variant summary: APC c.2627G>A (p.Arg876Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250804 control chromosomes, predominantly at a frequency of 8e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2627G>A has been reported in the literature in an individual(s) affected with breast cancer without strong evidence of causality (e.g. Guindalini_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27930734, 35264596, 35534704). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=7), likely benign (n=1) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Classic or attenuated familial adenomatous polyposis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces arginine with glutamine at codon 876 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with kidney cancer (PMID: 29684080). This variant has been identified in 15/282206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at